This proposal is for a five year renewal (years 6-10) of a Program Project to pursue gamma-secretase modulating compounds as Alzheimer's disease (AD) therapeutics at the University of California, San Diego, consortium with Mayo Clinic Jacksonville and Washington University, St Louis. In the first five years of support, we have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) have a novel secondary action that modulates gamma-secretase processing in a cyclooxygenase (COX) independent manner. The activity of a subset of NSAIDs preferentially lowers the amyloidogenic A[unreadable]42 peptide both in vitro and in vivo, leading us to propose that this activity may be one explanation for the apparent risk reduction of AD in chronic NSAID users. As we have identified many compounds in addition to NSAIDs that shift gamma secretase cleavage, we now generically refer to these compounds as gamma-secretase modulators (GSMs). Our research efforts have contributed to the introduction of the first GSM, R-flurbiprofen ("Flurizan" renamed Tarenflurbil") into the clinic for testing in AD treatment, and led to the preclinical development of additional GSMs. The two major goals of this PPG are to further understand the mechanism of action of GSMs, and to test their activity in humans as well as determine their ability to lower disease-associated biomarkers in AD individuals. Project 1 will examine the site of action of GSMs with respect to effects on gamma- versus epsilon-cleavage and test the efficacy of combination treatments in rodents. Project 2, which has now incorporated the former Chemistry Core, will extend studies relating to the binding site of multiple GSMs, examine the relative contribution of GSMs with respect to reducing A[unreadable]42 production vs. inhibiting A[unreadable] aggregation, and conduct animal studies to better define how GSMs acutely alter A[unreadable] levels in the brain, CSF, and plasma of mouse AD models. Projects 1 and 2 will coordinately examine the biological properties of shorter A[unreadable] peptides which are elevated by these GSMs. Project 3 will determine if R-flurbiprofen lowers A[unreadable]42 in human CSF by measuring newly synthesized A[unreadable] through in-dwelling catheter and will test whether a GSM (ibuprofen) will reduce disease associated CSF biomarkers and brain volumetric changes by neuroimaging in AD subjects in a one year placebo controlled double-blind treatment study. Successful completion of these studies will provide greater insight into 1) how the GSMs shift gamma cleavage, 2) how GSMs attenuate AD-like phenotypes in rodent models, and 3) how GSMs and GSM based NSAIDs may work in humans. By providing additional preclinical and clinical information on GAMs, such studies should contribute significantly to the further development of GSMs as Alzheimer's therapeutics. PRINCIPAL INVESTIGATOR: Dr. Edward Koo is a world renowned and experienced AD research. He is well qualified to lead this program project. REVIEW OF INDIVIDUAL COMPONENTS CORE A - Administrative Core, Dr. Edward Koo DESCRIPTION (provided by applicant): The responsibilities of the Administrative Core are to coordinate and integrate the activities of the three Projects to ensure maximum cooperation and coordination of efforts among program investigators. Further, the Core will provide administrative and financial support for the Projects on an ongoing basis. The Core will organize the annual visit of the External Advisory Committee to review the scientific progress of the Projects. The Core will interface with the Data Safety and Monitoring Board who will oversee the safety aspects of the clinical studies proposed in Project 3. Further, the Core will provide fiscal and management oversight of the Alzheimer's Disease Cooperative Study (ADCS) who will be directing the biomarkers study proposed in Project 3. Another goal of the Core is to enrich aging and Alzheimer's disease research by facilitating the dissemination of results and interaction with other investigators at UCSD, Mayo Clinic Jacksonville, and other local institutions. The Administrative Core is responsible for assuring compliance with animal welfare, scientific integrity, and financial policy requirements of UCSD and NIH. Lastly, the Core will be responsible to assembling the annual progress report to NIH.